Neuropeptide Y (NPY) is a 36 amino acid peptide that mediates a variety of physiological effects in humans and other mammals. This peptide was first isolated by Tatemoto et al. (Nature (1982) 296:659) and subsequently found to be largely conserved across mammalian species. It belongs to a large family of peptides that includes, among others, peptide YY (PYY) and pancreatic peptide (PP). NPY is the most abundant peptide in the mammalian brain, and is also present in sympathetic neurons. In addition, NPY-containing fibers have been found in peripheral tissues, such as around the arteries in the heart, the respiratory tract, the gastrointestinal tract and the genitourinary tract.
Central injection of NPY elicits a multitude of physiological responses, such as stimulation of feeding, increase in fat storage, elevation of blood sugar and insulin, anxiolytic behaviors, reduction in locomotor activity, hormone release, increase in blood pressure, reduction in body temperature and catalepsy. In the cardiovascular system, NPY appears to be involved in the regulation of coronary tone. These effects are selectively mediated by various NPY receptors, which currently include the Y1, Y2, Y3, Y4, Y5 and Y6 subtypes, as well as the hypothetical Y1-like subtype (e.g., Wahlestedt and Reis (1993) Ann. Rev. Pharmacol. Toxicol. 33:309; Gehlert and Hipskind (1995) Curr. Pharm. Design, 1:295; Michel et al. (1998) Pharmacol. Rev. 50:143).
The Y5 receptor subtype (e.g., U.S. Pat. No. 5,602,024) appears to be involved in appetite regulation, including the modulation of food intake and energy expenditure. In addition, studies of seizure-prone mice have suggested that the NPY5 receptor may have an anti-epileptic activity in the control of limbic seizures. NPY5-like receptors have also been implicated in attenuation of morphine withdrawal symptoms, enhancement of diuresis and natriuresis, lowering of blood glucose, inhibition of luteinizing hormone secretion, and reduction of acetylcholine release in the ileum. See, for example, Hu et al.(1996) J. Biol. Chem., 271:26315–19; Gerald et al.(1996) Nature, 382:168–71; Blomquist et al. (1997) TINS, 20: 294–98.
Selective peptide agonists and antagonists have been identified for most of the NPY receptor subtypes. Peptides, however, generally have serious shortcomings for therapeutic use including, poor metabolic stability, low oral bioavailability and poor brain permeability. To date, few non-peptide antagonists have been reported. WO 01/44201 describes certain substituted imidazole NPY receptor antagonists, but additional antagonists with improved properties are needed as therapeutic agents for the treatment of physiological disorders associated with NPY5 receptor activation, such as feeding disorders (e.g., obesity and bulemia), psychiatric disorders, diabetes and cardiovascular diseases (such as hypertension). The present invention fulfills this need, and provides further related advantages.